molecules Review Strategies for the Preparation of Phosphorus Janus Dendrimers and Their Properties Joel Cejas-Sánchez 1,2,3 , Anna Kajetanowicz 1 , Karol Grela 1 , Anne-Marie Caminade 4,5, * and Rosa María Sebastián 2,3, * 1 Biological and Chemical Research Centre, Faculty of Chemistry, University of Warsaw, Żwirki i Wigury 101, 02-089 Warsaw, Poland; j.cejassanch@student.uw.edu.pl (J.C.-S.); a.kajetanowicz@uw.edu.pl (A.K.); klgre@uw.edu.pl (K.G.) 2 Department of Chemistry, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Bellaterra, 08193 Barcelona, Spain 3 Centro de Innovación en Química Avanzada (ORFEO-CINQA), Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Bellaterra, 08193 Barcelona, Spain 4 Laboratoire de Chimie de Coordination du CNRS, 205 Route de Narbonne, BP 44099, CEDEX 4, 31077 Toulouse, France 5 Université de Toulouse, UPS, INPT, CEDEX 4, 31077 Toulouse, France * Correspondence: anne-marie.caminade@lcc-toulouse.fr (A.-M.C.); rosamaria.sebastian@uab.cat (R.M.S.) Abstract: Dendrimers, being highly branched monodispersed macromolecules, predominantly ex- hibit identical terminal functionalities within their structural framework. Nonetheless, there are instances where the presence of two distinct surface functionalities becomes advantageous for the fulfilment of specific properties. To achieve this objective, one approach involves implementing Janus dendrimers, consisting of two dendrimeric wedges terminated by dissimilar functionalities. The prevalent method for creating these structures involves the synthesis of dendrons that possess a core functionality that complements that of a second dendron, facilitating their coupling to generate the desired dendrimers. In this comprehensive review, various techniques employed in the fabrication of phosphorus-based Janus dendrimers are elucidated, displaying the different coupling methodologies Citation: Cejas-Sánchez, J.; employed between the two units. The advantages of phosphorus dendrimers over classic dendrimers Kajetanowicz, A.; Grela, K.; will be shown, as the presence of at least one phosphorus atom in each generation allows for the easy Caminade, A.-M.; Sebastián, R.M. monitoring of reactions and the confirmation of purity through a simple technique such as 31 P NMR, Strategies for the Preparation of as these structures typically exhibit easily interpretable patterns. Phosphorus Janus Dendrimers and Their Properties. Molecules 2023, 28, Keywords: phosphorus chemistry; Janus dendrimers; dendrons; 31 P NMR spectroscopy 5570. https://doi.org/10.3390/ molecules28145570 Academic Editors: Jean-Luc Montchamp and Karen R. Winters 1. Introduction Received: 29 June 2023 Dendrimers are highly branched macromolecules characterized in most cases by a Revised: 17 July 2023 spherical shape. This unique class of polymers is often constructed through step-by-step Accepted: 18 July 2023 reactions, starting from a polyfunctional core and progressively growing over generations. Published: 21 July 2023 At each generation, new branching points are introduced, leading to an exponential increase in the number of terminal functional groups [1,2]. Dendrimers have garnered significant attention in the scientific literature and are considered versatile systems with a wide range of applications in various fields such as biology [3], biomedicine [1,4], material science [5,6], Copyright: © 2023 by the authors. catalysis [7–9], or sensors [10,11], among others. However, the functionalization of den- Licensee MDPI, Basel, Switzerland. drimer surfaces has been predominantly limited to a uniformity of functional groups, This article is an open access article restricting their applicability to a single specific area. distributed under the terms and To overcome this limitation and enable the incorporation of multiple types of termi- conditions of the Creative Commons nal groups on dendrimer surfaces, several methodologies have been developed. These Attribution (CC BY) license (https:// approaches allow for the introduction of various functional groups, enabling the synthesis creativecommons.org/licenses/by/ of dendrimers with combined properties within a single molecule. One common method 4.0/). Molecules 2023, 28, 5570. https://doi.org/10.3390/molecules28145570 https://www.mdpi.com/journal/molecules Molecules 2023, 28, x FOR PEER REVIEW 2 of 19 Molecules 2023, 28, 5570 2 of 18 involvesgrafting involves graftingtwotwotypes typesof offunctions functionson onthe thesurface, surface,either eitherininaastochastic stochasticor orprecise precise manner, by sequentially reacting one functionality atop another in manner, by sequentially reacting one functionality atop another in a stepwise synthesis [12].a stepwise synthesis [12]. However, However, the most the most intriguing intriguing approach approach involves involves the preparation the preparation of dendrimers of dendrimers with with a a multifunctional surface using dendrimeric structures composed multifunctional surface using dendrimeric structures composed of two dendrons (wedge- of two dendrons (wedge-shaped shaped dendrimericdendrimeric units) athrough units) through central acore central core coupling coupling [13,14]. [13,14]. These These struc- structures are tures are commonly commonly referred to referred as Janus to as Janus dendrimers dendrimers [15], named[15],afternamed the Romanafter god the Roman god of of transitions transitions and and depicted beginnings, beginnings,withdepicted two faces with two faces oriented oriented in opposite in opposite directions. It isdirections. worth notingIt is worth noting that Janus dendrimers have also been referred to by that Janus dendrimers have also been referred to by different names in the literature, such different names in the literature, such as surface block dendrimers as surface block dendrimers [16] or di-block dendrimers [17].[16] or di-block dendrimers [17]. Threemain Three main methodologies methodologies have have beenbeen developed developed for theforsynthesis the synthesis of Janusofdendrimers, Janus den- drimers, as depicted as in depicted Scheme in1.Scheme These1.methods These methodsinvolveinvolve either theeither the reaction reaction of twoofdendrons two den- drons with with complementary complementary functionsfunctions at thelevel at the core core(method level (method i); the i); the sequential sequential reaction reaction of a of adendron first first dendron with with a well-defined a well-defined core, core, followed followed by grafting by grafting a second a second dendrondendron onto onto the the remaining core functions (method ii); or the divergent growth remaining core functions (method ii); or the divergent growth of new branches from a focal of new branches from a focal point of point of a dendron a dendron (method(method iii). iii). Scheme1.1.Schematic Scheme Schematicrepresentation representationofofthe themain mainmethods methodstotosynthesize synthesizeJanus Janusdendrimers dendrimerswith withtwo two functionalities at the surface. functionalities at the surface. Janusdendrimers Janus dendrimers have have been been the thesubject subjectofofinterest interestsince their since first their description first by Fré- description by chet et al. in 1991 [18]. In their pioneering work, a Janus dendrimer Fréchet et al. in 1991 [18]. In their pioneering work, a Janus dendrimer was synthesized was synthesized throughaaconvergent through convergentapproach approachby bycoupling couplingtwotwopoly(benzyl poly(benzylether) ether)(PBzE) (PBzE)dendrons. dendrons.OneOne dendron,owning dendron, owningaabenzylbenzylbromide bromidegroup, group,waswasgrafted graftedonto ontoaapolyphenolic polyphenoliccore corethrough through aamonosubstitution monosubstitutionreaction reactionunder underbasic basicconditions, conditions,resulting resultingininananAB AB2 -type 2-typecore core(one (one functiondifferent function differentfromfromthethetwo twoothers). others).The Theremaining remainingunreacted unreactedphenol phenolgroups groupson onthe the core were then reacted with other dendrons possessing different functionalities core were then reacted with other dendrons possessing different functionalities to complete to com- plete the the synthesis synthesis of the dendrimer of the Janus Janus dendrimer (Scheme(Scheme 2). 2). Thesynthesis The synthesisofofPBzEPBzEJanus Janusdendrimers dendrimersvia viasubstitution substitutionreactions reactionsinvolving involvingphenols phenols andbenzylic and benzylic halides has has been been widely widelyemployed employedininthe literature. the ThisThis literature. approach has has approach ena- bled thethe enabled creation of Janus creation of Janusdendrimers dendrimers with benzyl/carboxylate with benzyl/carboxylate terminal groups terminal or ben- groups or benzyl/nitrile functionalities zyl/nitrile functionalities [19].[19]. TheseThese PBzE PBzE Janus dendrimers Janus dendrimers have diverse have found found diverse applica- applications, tions, such assuch the as the formation formation of liquid of liquid membranes membranes for organic/water for organic/water interphase interphase systems systems and theand the modification modification of polymer of polymer properties properties in terms in terms of dipole of dipole moment moment [20] [20] or or glass glass tran- transition temperatures sition temperatures [21], [21], among among others. others. Molecules 2023,28, Molecules 2023, 28,5570 x FOR PEER REVIEW 33 of of 18 19 Scheme 2. Scheme 2. Synthetic Synthetic strategy strategy for for the the preparation preparation of of aa PBzE PBzE Janus Janus dendrimer with aa polyphenol dendrimer with polyphenol core, core, based on method ii. based on method ii. Interestingly, aa polymerizable Interestingly, polymerizable PBzEPBzE Janus Janus dendrimer dendrimerwas wasalso alsosynthesized synthesizedusing usinga similar method, wherein a dendron terminated with oligoethylene (OEG) a similar method, wherein a dendron terminated with oligoethylene (OEG) chains was chains was re- acted with a second dendron ended with benzyl groups and possessing a dibromoben- reacted with a second dendron ended with benzyl groups and possessing a dibromobenzene zeneatunit unit coreat(Figure core (Figure 1). Later, 1). Later, this dibromobenzene this dibromobenzene groupgroup was reacted was reacted with with diboronic diboronic acid acid in in a polycondensation a polycondensation reaction reaction to afford to afford the desired the desired polymeric polymeric structure structure [22]. [22]. In addition to PBzE dendrimers, classic poly(amidoamine) (PAMAM) structures have also been used for the synthesis of Janus dendrimers. For instance, Aoi et al. [23] demon- strated the synthesis of a Janus dendrimer by grafting a dendron bearing a primary amine core and terminated with sugar chains onto a second PAMAM dendron possessing ph- thaloyl groups on the surface through the formation of a urea linker by a reaction between a carbamoyl chloride and a primary amine (Scheme 3). They can be potentially used in the fields of supramolecular self-assembly or biology and biomedicine by means of binding surface sectors to proteins and DNA. Figure 1. PBzE Janus dendrimer holding OEG chains on one side and bromine atoms at the core to be used as polymerization points, synthesized by method i. based on method ii. Interestingly, a polymerizable PBzE Janus dendrimer was also synthesized using a similar method, wherein a dendron terminated with oligoethylene (OEG) chains was re- acted with a second dendron ended with benzyl groups and possessing a dibromoben- Molecules 2023, 28, 5570 4 of 18 zene unit at core (Figure 1). Later, this dibromobenzene group was reacted with diboronic acid in a polycondensation reaction to afford the desired polymeric structure [22]. Molecules 2023, 28, x FOR PEER REVIEW 4 of 19 In addition to PBzE dendrimers, classic poly(amidoamine) (PAMAM) structures have also been used for the synthesis of Janus dendrimers. For instance, Aoi et al. [23] demonstrated the synthesis of a Janus dendrimer by grafting a dendron bearing a primary amine core and terminated with sugar chains onto a second PAMAM dendron possessing phthaloyl groups on the surface through the formation of a urea linker by a reaction be- tween a carbamoyl chloride and a primary amine (Scheme 3). They can be potentially used in the 1. Figure Figure fields 1. PBzEof PBzE supramolecular Janus Janus dendrimer self-assembly dendrimer holding holding chainsor OEG chains OEG onbiology on sideand one side one biomedicine and bromine and atomsby bromine atoms means at the at the of core to core to be used binding be as polymerization used assurface points, sectors to polymerization synthesized proteins points, by and DNA. synthesized method i. by method i. Scheme 3. Scheme 3. PAMAM PAMAM Janus Janus dendrimer dendrimer bearing bearing phthaloyl phthaloyl groups groups on on one one side side and and sugars sugars on on the the other, other, prepared by method i. prepared by method i. An intriguing An intriguing Janus Janus dendrimer dendrimerwaswas recently recentlydesigned designedby byRosati Rosatietet al. al. [24], [24], employing employing a novel linker using “click” chemistry (Scheme 4). A dendrimer was obtained a novel linker using “click” chemistry (Scheme 4). A dendrimer was obtained through through aa copper-catalyzed azide–alkylidene reaction where two dendrons—either copper-catalyzed azide–alkylidene reaction where two dendrons—either with an with an azide azideor anan or acetylene group—were acetylene group—were coupled coupledthrough the formation through of a triazole. the formation The obtained of a triazole. Janus The obtained dendrimers Janus displayed dendrimers a tuning displayed of theirof a tuning self-assembly properties their self-assembly by dispersion properties in aqueous by dispersion in solution solution aqueous and were andtargeted for applications were targeted such assuch for applications the transport of gases as the transport or 19F or of gases 19 F NMR tracking NMR in MRI tracking in(Magnetic Resonance MRI (Magnetic Imaging). Resonance Imaging). Molecules 2023, Molecules 2023, 28, 28, 5570 x FOR PEER REVIEW 5 5of of 19 18 Scheme 4. Fluorinated Janus dendrimer synthesized by “click” reaction of two dendrons containing Scheme 4. Fluorinated Janus dendrimer synthesized by “click” reaction of two dendrons containing azide and acetylene moieties, based on method i. azide and acetylene moieties, based on method i. The examples mentioned above provide only a glimpse into the extensive literature The examples mentioned above provide only a glimpse into the extensive literature available available on on Janus Janus dendrimers. dendrimers. These These structures structures have have been been extensively extensively explored, explored, resulting resulting in in diverse compositions. For comprehensive reviews of the synthesis and properties of diverse compositions. For comprehensive reviews of the synthesis and properties of Janus Janus dendrimers, refer to dendrimers, refer to the the work work by by Caminade Caminade et et al. al. [14] [14] and and Căta Căta etet al. al. [25]. [25]. Although known, Janus Although known, Janus dendrimers dendrimers incorporating incorporatingphosphorus phosphorusatoms atomsatatallallbranch- bran- ching points remain relatively unexplored, but hold enormous potential ing points remain relatively unexplored, but hold enormous potential in various fields.in various fields. This comprehensive review This comprehensive review aims aims to to present present different synthetic approaches different synthetic approaches to to produce produce phosphorus-based Janus dendrimers, focusing on various coupling strategies phosphorus-based Janus dendrimers, focusing on various coupling strategies employed employed to to construct construct the the desired desired di-block di-block structures, structures, asas well well as as the the targeted targeted applications applications for for these these compounds. In addition, the main characterization technique for this type compounds. In addition, the main characterization technique for this type of dendrimer, of dendrimer, 31PPNMR, 31 NMR,will willbe behighlighted highlighted for for the the different different syntheses. syntheses. 2. Phosphorus Dendrimers Built via Vinyl/Amine Coupling The pioneering work of the group of Caminade and Majoral presented the first Janus dendrimer incorporating phosphorus atoms at each branching point. The dendrimer was synthesized by combining two dendrons, each possessing a complementary functionality at the core level. Initially, Initially, polyphosphorhydrazone polyphosphorhydrazone(PPH) (PPH)dendrons dendronswereweresynthesized synthesizedvia viaa adivergent divergentprocess, process,featuring featuringaavinyl vinylgroup groupatatthe thecore coreand and various various functional functional groups on the surface (Scheme 5a) [26]. The The vinyl vinyl groups groups were were subsequently subsequently converted converted toto amine- amine- terminated dendrons through a reaction with a diamine, allowing for subsequent dendrons through a reaction with a diamine, allowing for subsequent cou- coupling with another pling dendron. with another This synthetic dendron. approach This synthetic helpedhelped approach the formation of Janus the formation ofdendrimers Janus den- by linking two dendrons together via vinyl/amine coupling, as illustrated drimers by linking two dendrons together via vinyl/amine coupling, as illustrated in Scheme 6.in SchemeIn 2000, 6. Maraval et al. [27] reported the synthesis of multidendritic systems based on the Michael addition coupling of amines to dendrons, featuring a vinyl core. The Janus dendrimers were created using an AB2 -type monomer derived from thiophosphoryl chlo- ride through a two-step process involving the introduction of two benzaldehyde moieties and an azide group. The reaction between the azide terminus and diphenylvinyldiphos- phine yielded the desired vinyl core dendron with aldehyde functionalities on the surface. The growth of dendrons followed established methodologies for phosphorus dendrimer synthesis [28,29], involving a condensation reaction between the aldehyde groups and H2 NN(Me)P(S)Cl2 . Subsequent growth steps led to the dendrons’ formation, up to the third generation (Scheme 5a). The functionalization of the surface with various substituted phenolic salts resulted in fully characterized dendrons decorated with nitrile groups, phos- phines, or amines (Scheme 5b). Dendrons were characterized at each synthetic step using 1 H NMR, 31 P NMR, 13 C NMR, and IR techniques. Molecules Molecules2023, Molecules 28, 2023,28, 2023, xxFOR FORPEER 28,5570 PEERREVIEW REVIEW 66 6of of 19 of19 18 Scheme Scheme 5. 5. (a) 5. (a) Synthesis Synthesis of (a) Synthesis polyphosphorhydrazone dendrons bearing a avinyl group atatthe core upupto Scheme of polyphosphorhydrazone dendrons bearing bearing a vinyl vinyl group group at the the core core up the third to the to generation. the third (b) third generation. Schematic representation of the surface functionalization generation. (b) Schematic representation of the surface functionalization of PPH functionalization of dendrons, of PPH PPH den- den- introducing drons, aldehyde, drons, introducing introducing nitrile, nitrile, aldehyde, aldehyde, phosphine, or amino phosphine, or derivatives. amino derivatives. derivatives. Scheme 6. Synthesis Scheme Synthesis of polyphosphorhydrazone polyphosphorhydrazone Janus dendrimers with aa (1R,2R)-cyclohexane-1,2- Scheme 6. 6. Synthesis of of polyphosphorhydrazone Janus Janus dendrimers dendrimers with with a (1R,2R)-cyclohexane-1,2- (1R,2R)-cyclohexane-1,2- diamine core, based on method ii. diamine core, based on method ii. diamine core, based on method ii. In 2000, In 2000, Maraval Maraval et et al. al. [27] [27] reported reported thethe synthesis synthesis of of multidendritic multidendritic systems systems based basedon on Further advancements in Janus dendrimer synthesis involved coupling two dendrons the the Michael Michael addition addition coupling coupling of of amines amines to to dendrons, dendrons, featuring featuring a a vinyl vinyl core. core. The The Janus Janus with vinyl groups using the aforementioned diamine method. The vinyl moiety was reacted dendrimers were dendrimers were created created using using anan AB AB22-type -type monomer monomer derived derived fromfrom thiophosphoryl chlo- with an excess of the corresponding diamine (ethylenediamine or thiophosphoryl (1R,2R)-cyclohexane-chlo- ride ride through through a a two-step two-step process process involving involving the the introduction introduction of of two two benzaldehyde benzaldehyde moieties moieties 1,2-diamine) to obtain mono-addition products, which were subsequently reacted with a and an and an azide azide group. group. The The reaction reaction between between the azide azide terminus and diphenylvinyldiphos- second dendron to yield the desired di-blockthe dendrimers terminus (Scheme and 6). diphenylvinyldiphos- Evidence of successful phine phine yielded yielded thethe desired vinyl core dendron with aldehyde functionalities on the thesurface. core coupling wasdesired observedvinyl core dendron through with aldehyde an increased symmetryfunctionalities of the core, ason surface. confirmed by The 13 The growth of dendrons growthspectroscopy. followed of dendrons followed established methodologies establishedallowed methodologies for phosphorus for phosphorus dendrimer dendrimer C NMR This methodology for the synthesis of various Janus synthesis [28,29], synthesis dendrimers [28,29], containing involving involving aa condensation different condensation functional groups reaction reaction between between (nitriles, the the aldehyde phosphines, aldehyde groups groups or amines) and and on their HH 2NN(Me)P(S)Cl2. Subsequent growth steps led to the dendrons’ formation, up to the 2NN(Me)P(S)Cl surfaces by combining 2. Subsequent two typesgrowth steps led of functional to the dendrons’ formation, up to the groups. thirdIn third generation generation 2006, Maraval(Scheme (Scheme 5a). 5a). et al. The The [30] functionalization the sameof functionalization employed the the surface surface with ofvinyl/amine with various varioussubstituted methodology substituted to synthe- phenolic phenolic size salts resulted salts dendrimers resulted in fully in fully characterized with multi-charged characterized surfaces. dendrons dendrons Specifically, decorated decorated with with nitrile they described nitrile groups, groups, the synthesis phosphines, of polycationic, phosphines, or amines neutral, or amines (Scheme 5b). and polyanionic (Scheme Dendrons 5b). Dendrons were dendrons characterized by incorporating were characterized at each synthetic synthetic step ammonium at each tags, step using 11H using H NMR, carboxylic NMR, 31P NMR, 13C NMR, and IR techniques. acid 31groups, P NMR,and carboxylates 13C NMR, and IR on the surface of the dendrons, respectively. techniques. successful core coupling was observed through an increased symmetry of the core, as con- firmed by 13C NMR spectroscopy. This methodology allowed for the synthesis of various Janus dendrimers containing different functional groups (nitriles, phosphines, or amines) on their surfaces by combining two types of functional groups. In 2006, Maraval et al. [30] employed the same vinyl/amine methodology to synthe- Molecules 2023, 28, 5570 size dendrimers with multi-charged surfaces. Specifically, they described the synthesis 7 ofof 18 polycationic, neutral, and polyanionic dendrons by incorporating ammonium tags, car- boxylic acid groups, and carboxylates on the surface of the dendrons, respectively. The synthetic The approach synthetic approachto obtain dendrons to obtain dendronswas was previously previously described (refer(refer described to Scheme 5). The to Scheme 5). —P(S)Cl The —P(S)Cl2 terminus of the 2 terminus of vinyl dendrons the vinyl dendrons waswasmodified modified with the the with desired desiredfunctionalities functionalitiesto generate to generate polyionic polyionic systems, systems, which whichcould serve could as promising serve as promising candidates candidatesfor biological ap- for biological plications [31,32] applications oror [31,32] layer-by-layer layer-by-layer deposition deposition (see(see later). later). The synthesis The synthesis of polycationic dendrons (Scheme (Scheme 7) 7) involved involvedthe thereaction reactionof ofthe theden- den- driticmoieties dritic moietieswith withN,N-diethylethylenediamine N,N-diethylethylenediaminethrough throughaasubstitution substitutionreaction reactiontotoyield yielda a tetraammonium-functionalized tetraammonium-functionalized dendron. dendron. Hydrogen Hydrogen chloride chloride generated generated during during thethe pro- process cessquantitatively was was quantitatively captured captured by thebyterminal the terminalamines.amines. The The progression progression of theof reaction the reaction and andpurity the the purity of theofcompounds the compounds werewere evaluated evaluated using 31 P 31 using P NMR, NMR, as the as the coupling coupling withwith di- diethylethylenediamine ethylethylenediamine resulted resulted in ain a significant significant shiftshift of theofterminal the terminal phosphorus phosphorus atom atom signal signalδ from from = 63.4δ ppm = 63.4toppm to δ ppm. δ = 73.4 = 73.4 It ppm. It is important is important to emphasize to emphasize the usetheofuse of stoichio- stoichiometric metric quantities quantities of diethylethylenediamine of diethylethylenediamine to preventto prevent MichaelMichael addition addition at thecore. at the vinyl vinylSubse- core. quent treatment Subsequent with NaOH treatment with produced NaOH producedthe corresponding the correspondingtetraamine-terminated dendrons. tetraamine-terminated This strategy dendrons. was This employed strategy for higher-generation was employed dendrons,dendrons, for higher-generation leading toleading ammonium- and to ammo- amino-tagged dendrons up nium- and amino-tagged to the third dendrons up to generation. the third generation. Scheme 7. Scheme 7. Synthesis Synthesis of ofpolycationic, polycationic,neutral, neutral,and andpolyanionic dendrons polyanionic bearing dendrons a vinyl bearing group a vinyl at the group at core. the core. Polyanionic dendrons Polyanionic dendrons wereweresynthesized synthesizedthrough through a three-step a three-step surface functionaliza- surface functional- tion process ization process (Scheme (Scheme7). 7). TheThe—P(S)Cl 2 surface —P(S)Cl 2 of surface the of dendron the dendronwas reacted was with reacted 4-hy- with 4- droxybenzaldehyde under basic conditions, followed by a reaction hydroxybenzaldehyde under basic conditions, followed by a reaction with hydrazinewith hydrazine ben- zoic acidacid benzoic to yield dendrons to yield dendrons with carboxylic with acidacid carboxylic termini. Lastly, termini. treatment Lastly, withwith treatment NaHNaH re- sulted ininthe resulted theformation formationofofcarboxylate carboxylatedendrons. dendrons.The Theprogression progressionof ofthe the reactions reactions was was monitored using monitored using NMR NMR techniques. techniques. TheThe formation formation of of the the hydrazine hydrazine derivative derivativewaswascon- con- firmedby firmed by 11H NMR and IR, as indicated by the disappearance of of aldehyde aldehyde signals signals and and the the appearance of appearance of aa new new carboxylic carboxylic acid peak. 31 acid peak. 31P P NMR NMR was was used used to to confirm confirm the the integrity integrity of of the structure. the structure. After synthesizing polyanionic, polycationic, and neutral dendrons, Janus dendrimers were prepared by coupling two dendritic moieties through their respective cores. The amine-terminated dendron was reacted with ethylenediamine, undergoing a Michael addition on the vinyl group at the dendron’s core to introduce the desired functionalized core. Subsequently, the coupling of two dendrons possessing vinyl and amino groups at the core was achieved in a biphasic THF/water system by simply combining the two dendrons at 70 ◦ C (Scheme 8a). The progress of the reaction was monitored using 31 P NMR, as the reaction of the vinyl group linked to the P=N—P=S moiety induced notable shifts in the NMR signals. In particular, the 31 P NMR chemical shift for the P=N group moves from 14.7 ppm (d, 2 Jpp = 28.0 Hz) in the dendron to 21.7 ppm (d, 2 Jpp = 30.9 Hz) in the Janus dendrimer. This methodology enabled the synthesis of Janus dendrimers up to the third generation (Scheme 8b). In particular, Janus dendrimers of the hybrid generation were also obtained by combining dendrons of different generations [30]. drons at 70 °C (Scheme 8a). The progress of the reaction was monitored using 31P NMR, as the reaction of the vinyl group linked to the P=N─P=S moiety induced notable shifts in the NMR signals. In particular, the 31P NMR chemical shift for the P=N group moves from 14.7 ppm (d, 2Jpp = 28.0 Hz) in the dendron to 21.7 ppm (d, 2Jpp = 30.9 Hz) in the Janus dendrimer. This methodology enabled the synthesis of Janus dendrimers up to the third Molecules 2023, 28, 5570 8 of 18 generation (Scheme 8b). In particular, Janus dendrimers of the hybrid generation were also obtained by combining dendrons of different generations [30]. Scheme8.8. (a) Scheme (a) Synthesis Synthesis of of aa polyanionic polyanionic Janus Janus dendrimer dendrimer through through amine/vinyl amine/vinyl core–core core–core coupling coupling of two second-generation dendrons using method ii. (b) Linear representation of the third-genera- of two second-generation dendrons using method ii. (b) Linear representation of the third-generation tion Janus dendrimer with the same structural pattern. Janus dendrimer with the same structural pattern. Lastly,the Lastly, theauthors authorsdemonstrated demonstrated thethe applicability applicability of of thethe polycationic polycationic andand polyan- polyanionic ionic Janus dendrimers for layer-by-layer deposition. As previously Janus dendrimers for layer-by-layer deposition. As previously shown by Kim et al. shown by Kim et al. in in 2005 [33], polyionic dendrimers can be employed to prepare nanotubes 2005 [33], polyionic dendrimers can be employed to prepare nanotubes and microcapsules and microcap- sules by by alternately alternately depositing depositing layers layers of of polyanionic polyanionic and polycationic and polycationic dendrimers. dendrimers. Pre- Preliminary liminary results indicated the successful deposition of a polyanionic Janus dendrimer results indicated the successful deposition of a polyanionic Janus dendrimer onto a silica onto a silica pre-coated surface surface pre-coated with a monolayer with a monolayer of 3-aminopropyl of 3-aminopropyl dimethylethoxy dimethylethoxy silane. silane. Similar Similar to to the dendrimer the dendrimer depicted depicted in Scheme in Scheme 9, the9,deposition the deposition of anionic of anionic dendrimers dendrimers ontoa onto a positively charged surface occurred through electrostatic interactions, resulting positively charged surface occurred through electrostatic interactions, resulting in a neutralin a neu- tral surface. The amine terminus was subsequently quaternarized with surface. The amine terminus was subsequently quaternarized with methyl iodide as an methyl iodide as an alkylating agent to generate a positively charged surface, which was then alkylating agent to generate a positively charged surface, which was then covered with covered with the polyanionic the polyanionic dendron dendron part part of of the the Janus Janus dendrimer dendrimer to to assemble assemble the the second second layer. layer. ByBy repeating this methodology, a thin film was constructed based on the quaternization and adsorption sequences, allowing for the deposition of up to four layers and the creation of nano-objects with potential applications in surface modification. The spectroscopic and microscopic characterization of these systems was conducted by Lee et al. [34]. UV–visible spectroscopy and atomic force microscopy (AFM) analyses confirmed the uniform formation of films over the entire substrate area, with a consistent increase in film thickness. Molecules 2023, 28, x FOR PEER REVIEW 9 of 19 repeating this methodology, a thin film was constructed based on the quaternization and Molecules 2023, 28, 5570 9 of 18 adsorption sequences, allowing for the deposition of up to four layers and the creation of nano-objects with potential applications in surface modification. Scheme 9. Representation of the interactions between polyionic Janus dendrimers assembled in Scheme 9. Representation of the interactions between polyionic Janus dendrimers assembled in multilayer systems for applications in materials science. multilayer systems for applications in materials science. The spectroscopic 3. Synthesis and microscopic of Dendrimers characterization via Staudinger Reaction of these systems was conducted by Lee et al. [34]. UV–visible spectroscopy and atomic force microscopy (AFM) analyses The Staudinger reaction is exceptionally versatile in the realm of synthetic chemistry, confirmed the uniform formation of films over the entire substrate area, with a consistent primarily employed for the synthesis of iminophosphoranes through the reaction between increase an in film azide and thickness. a phosphine/phosphite [35]. Notably, these reactions typically occur under ambient conditions with simple reaction parameters, leading to high conversions and 3. Synthesis of Dendrimers via Staudinger Reaction negligible by-products other than nitrogen gas. These unique characteristics have rendered The Staudinger the Staudinger reactionreaction is exceptionally an outstanding versatile methodology forinthe thesynthesis realm ofof synthetic intricatechemistry, molecular primarily employed structures [36–38]. for the synthesis of iminophosphoranes through the reaction between an azide In theand a phosphine/phosphite context of dendrimer synthesis, [35]. Notably, these reactions the Staudinger typically reaction has foundoccur under application ambient as well. conditions with simple In 2001, Brauge et al. reaction parameters, [39] reported leading tosynthesis the divergent high conversions and neg- of a phosphorus ligible by-products dendrimer, otheran incorporating than nitrogen gas. in iminophosphine These unique characteristics its branches. In this approach, have rendered an aldehyde- terminated monomer was reacted with a phosphorhydrazide dendron to yield molec- the Staudinger reaction an outstanding methodology for the synthesis of intricate a first- ular structures generation [36–38]. dendrimer through condensation reactions, resulting in a dendrimer possessing In the context six terminal of dendrimer synthesis, diphenylphosphine the Staudingerphosphine groups. Subsequently, reaction has foundwere groups application reacted as well. with In 2001, Brauge a functionalized et al. azide [39] the using reported the divergent Staudinger reaction,synthesis leading to ofthe a phosphorus formation of den- the drimer, incorporating second-generation an iminophosphine dendrimer (Scheme 10).in its branches. In this approach, an aldehyde- terminated Gottis etmonomer was reacted al. [40] employed with a strategy a similar phosphorhydrazide dendron for the coupling to yield atofirst-gen- of dendrons produce eration dendrimer through condensation reactions, resulting in Janus dendrimers. They reported the synthesis of a hybrid carbosilane/PPH dendrimera dendrimer possessing six terminal through diphenylphosphine the formation groups. Subsequently, of an iminophosphine phosphine bond. One dendron groupsa were featured reacted thiophospho- with ryl a functionalized azide group at theazide core, using the Staudinger terminated with—P(S)Clreaction, leading 2 groups, to the while theformation of the other dendron second-generation possessed a phosphinedendrimer moiety (Scheme at the core10). and SiMe3 terminal groups. These two dendritic units were successfully coupled at room temperature, yielding the desired Janus dendrimer (Scheme 11). The reaction progress was monitored using 31 P{1 H} NMR, which revealed the formation of the iminophosphine bond and the generation of a P=N–P=S system through the appearance of distinct signals at δ = 51.9 ppm and δ = 19.8 ppm, corresponding to P=S and P=N, respectively. Janus dendrimers were synthesized up to the second generation using this method. Molecules 2023,28, Molecules2023, 28,5570 x FOR PEER REVIEW 10 of 10 of 18 19 Molecules 2023, 28, xScheme FOR PEER 10.REVIEW Synthesisofofa second-generation a second-generation polyphosphorhydrazone (PPH) dendrimer by func- 11 Scheme 10. Synthesis polyphosphorhydrazone (PPH) dendrimer by function- tionalization alization of theofbranches the branches through through Staudinger Staudinger reaction. reaction. Gottis et al. [40] employed a similar strategy for the coupling of dendrons to produce Janus dendrimers. They reported the synthesis of a hybrid carbosilane/PPH dendrimer through the formation of an iminophosphine bond. One dendron featured a thiophos- phoryl azide group at the core, terminated with—P(S)Cl2 groups, while the other dendron possessed a phosphine moiety at the core and SiMe3 terminal groups. These two dendritic units were successfully coupled at room temperature, yielding the desired Janus den- drimer (Scheme 11). The reaction progress was monitored using 31P{1H} NMR, which re- vealed the formation of the iminophosphine bond and the generation of a P=N–P=S sys- tem through the appearance of distinct signals at δ = 51.9 ppm and δ = 19.8 ppm, corre- sponding to P=S and P=N, respectively. Janus dendrimers were synthesized up to the sec- ond generation using this method. Scheme 11. Synthesis of a hybrid carbosilane/PPH Janus dendrimer (based on method Scheme 11. Synthesis of a hybrid carbosilane/PPH Janus dendrimer (based on method i) via Staudinger reaction, and the functionality of its surface to accommodate aldehyde and phos Staudinger reaction, and the functionality of its surface to accommodate aldehyde and phosphine groups. groups. The resulting Janus dendrimers were subsequently functionalized through the pres- The resulting ence of —P(S)Cl2 groups on theirJanus dendrimers surfaces. were subsequently By subjecting functionalized the dendrimers through the to basic condi- ence of —P(S)Cl 2 groups on their surfaces. By subjecting the dendrimers to basic c tions, they were functionalized with 4-hydroxybenzaldehyde moieties, allowing for the tions, reactivity of the theytowere system functionalized be assessed. with 4-hydroxybenzaldehyde The substitution moieties,was of the —P(S)Cl2 groups allowing fo reactivity of the system to be assessed. The substitution of the —P(S)Cl monitored using NMR spectroscopy, which indicated a downfield shift from δ = 63.4 ppm 2 groups was itored (for unsubstituted using NMR —P(S)Cl spectroscopy, which indicated a downfield shift from δ = 63.4 ppm 2 ) to δ = 70.0 ppm upon the monosubstitution of the phospho- unsubstituted —P(S)Cl2) to δ = 70.0 ppm upon the monosubstitution of the phosp atom with the phenol of interest to a —P(S)Cl(OR) system. This substitution pattern mately led to the disappearance of the signal at δ = 70.0 ppm, which was replaced singlet at δ = 60.7 ppm, corresponding to the fully substituted species. The same me ology was applied to incorporate other ligands, such as tyramine functionalized wit Molecules 2023, 28, 5570 11 of 18 rus atom with the phenol of interest to a —P(S)Cl(OR) system. This substitution pattern ultimately led to the disappearance of the signal at δ = 70.0 ppm, which was replaced by a singlet at δ = 60.7 ppm, corresponding to the fully substituted species. The same methodology was applied to incorporate other ligands, such as tyramine functionalized with two methylene bisdiphenylphosphines, demonstrating a consistent substitution pat- tern (Scheme 11). These novel phosphine-terminated carbosilane/PPH dendrimers were synthesized with the intention of their potential applications in catalysis in supercritical CO2 , owing to the coordinating ability of the phosphine ligands present on the Janus dendrimer’s surface. Interestingly, Maraval et al. [27] described the synthesis of a novel multiblock den- drimer by anchoring a dendron via Staudinger reaction to a previously obtained Janus dendrimer. It was synthesized using the methodology described in Scheme 6. Notably, a Janus dendrimer bearing terminal phosphine groups on one side was utilized for the synthesis of the mentioned multiblock system. As shown in Scheme 12, an azido den- drimer, which served as a building block for the preparation of the Janus dendrimers, was incorporated into the phosphine branches of the dendrimer, forming a P=N—P=S linkage. This demonstrated the versatility of the novel phosphine-ended Janus dendrimers Molecules 2023, 28, x FOR PEER REVIEW 12 of 19 in terms of their derivatization opportunities, yielding to the obtention of highly structural complex systems. Scheme 12. Scheme 12. Synthesis Synthesisof ofaamultiblock multiblockJanus Janusdendrimer, dendrimer, with with a dendron a dendron anchored anchored at the at the surface surface of of the the Janus dendrimer via “click” Staudinger reaction, based on method Janus dendrimer via “click” Staudinger reaction, based on method iii. iii. In 2001, In 2001, aa novel novel methodology methodology for for the the synthesis synthesis of of core–core-built core–core-built Janus Janus dendrimers dendrimers through Staudinger through Staudingerreaction reactionwas wasreported. reported.The Theprocess processinvolved involvedalkylation alkylationand andthe the sub- subse- sequent desulfurization of a dendron P=N─P=S core, followed by a Staudinger quent desulfurization of a dendron P=N—P=S core, followed by a Staudinger reaction with reaction awith a second second desireddesired dendron dendron [41].initial [41]. The The initial dendron dendron was constructed was constructed basedbased on anonABan AB2 2 core core comprising comprising two benzaldehyde two benzaldehyde groupsgroups and an and an azide azide [42]. These [42]. These functional functional groups groups were later wereon modified later through on modified the Staudinger through reactionreaction the Staudinger with H2with NN(Me)P(S)Cl 2 and the H2NN(Me)P(S)Cl desired 2 and the phosphine, resulting in desired phosphine, the formation resulting in the offormation a first-generation dendritic moiety of a first-generation (Scheme dendritic 13). moiety The 13). (Scheme first-generation dendron was then employed in a novel approach to generate Janus dendrimers through a desulfurization reaction of the —P=S group at the core. As depicted in Scheme 13, the dendron was subjected to the alkylation of the sulfur atom at the core using methyl triflate. The success of this crucial step was confirmed by 31 P NMR spectroscopy, which revealed the presence of two doublets at δ = 23.8 ppm and δ = 24.1 ppm (2 JPP = 18.2 Hz), corresponding to the P=N—P—S—Me linkage, as well as a singlet at δ = 62.8 ppm for the terminal —P(S)Cl2 group. Subsequently, ionic exchange with NaBPh4 and a functionalization of the —P(S)Cl2 group with N,N-diethylethylenediamine were conducted to obtain a polycationic dendron, enabling solubility in a range of solvents, including water. The cationic dendron was further reacted with P(NMe2 )3 to achieve the Janus dendrimer via “click” Staudinger reaction, based on method iii. In 2001, a novel methodology for the synthesis of core–core-built Janus dendrimers through Staudinger reaction was reported. The process involved alkylation and the sub- sequent desulfurization of a dendron P=N─P=S core, followed by a Staudinger reaction Molecules 2023, 28, 5570 with a second desired dendron [41]. The initial dendron was constructed based on an 12 AB of 18 2 core comprising two benzaldehyde groups and an azide [42]. These functional groups were later on modified through the Staudinger reaction with H2NN(Me)P(S)Cl2 and the desulfurization. desired phosphine,This resulting reaction was confirmed in the by 31of formation P NMR, which displayed a first-generation two doublets dendritic moiety at δ = 144.2 2 ppm and δ = 10.3 ppm ( JPP = 31.6 Hz), corresponding to the core signals. (Scheme 13). Scheme 13. Scheme 13. Synthesis Synthesis ofof aa PPH PPH Janus Janus dendrimer dendrimer via via aa novel novel desulfurization desulfurization methodology methodology and and Staudinger reaction, following method iii. Staudinger reaction, following method iii. The activated The first-generation dendron desulfurized corewas thenasemployed served the platformin afornovel approach coupling to generate a second dendron through a Staudinger reaction with a monomer containing two benzaldehydecore. Janus dendrimers through a desulfurization reaction of the —P=S group at the As groups depicted in Scheme 13, the dendron was subjected to the alkylation of and a reactive azide. This coupling led to the formation of a novel P=N—P=N—P=S the sulfur atom at the core using methyl triflate. The success of this crucial step was confirmed core linkage. The resulting Janus dendrimer was utilized for reaction with a di-iron by 31P NMR nonacarbonyl compound. To achieve this, the aldehyde groups were reacted with excess methylhydrazine, followed by treatment with Ph2 PCH2 OH, yielding a dendrimer with terminal phosphine groups. Potentially, the prepared dendrimer containing phosphine groups at the surface could be used for the complexation of metals, such as palladium, for their potential applications in catalysis. Finally, the desired Janus dendrimer with ammonium tags and incorporating iron complexes (Fe(CO)4 ) attached to a phosphine was obtained (Scheme 13). The formation of the Fe@dendrimer was confirmed by a significant deshielding of the phosphine signal, shifting from δ = -22.9 ppm to δ = 67.5 ppm [38]. 4. Synthesis via Coupling of AB5 Cyclotriphosphazene Systems AB5 compounds derived from the reactivity of hexachlorocyclotriphosphazene pos- sess one function different from the five others. Such types of compounds have garnered significant attention in the scientific literature due to their facile syntheses [43]. The syn- thetic approach for generating these dendrons involves the asymmetric functionalization of the core [44], resulting in type compounds denoted as “A” and “B.” The “A” group serves as a linkage point for coupling with another dendron, while the “B” group represents the functional terminal groups. The synthetic methodologies employed to achieve the desired AB5 systems are diverse, and stem from two distinct approaches based on the substitution of the N3 P3 Cl6 core: either five P—Cl bonds are reacted with one reagent and then the last one with a second reagent, or vice versa, by first reacting one Cl with one reagent and the remaining five with a second reagent. The asymmetry of these compounds has led to the Molecules 2023, 28, 5570 13 of 18 development of a great range of dendrons and dendritic structures, yielding to a plethora of compounds with different applications [45]. For a comprehensive review of the syntheses and applications of AB5 derivatives in the creation of phosphorus dendrons within the fields of biology, material science, catalysis, and sensors, refer to Zibarov et al. [45]. An intriguing example is the work described by Martinez-Ferrero et al. [46], wherein dendrimers were synthesized as hybrid optical sensors grafted onto mesoporous titania nanocomposites. An AB5 dendron was synthesized using N3 P3 Cl6 in a two-step process: first, the core was reacted with one equivalent of 4-hydroxybenzaldehyde to achieve the monosubstitution of one P—Cl bond, and second, the remaining five P—Cl bonds were reacted with maleimide-based phenolic chromophores. The successful substitution was confirmed through NMR and IR spectroscopy. The 1 H and 13 C NMR spectra exhibited multiple signals due to the asymmetric arrangement of the dendron branches around the core. The AB5 core was subsequently functionalized with H2 NN(Me)P(S)Cl2 to enable the further modification of the dendritic structure. The terminal —P(S)Cl2 group was decorated Molecules 2023, 28, x FOR PEER REVIEW 14 of 19 with various phosphonate groups, known for their stability in forming complexes with metal oxides (Scheme 14). Scheme14. Scheme 14.Functionalization Functionalizationofofa apolyphosphorhydrazone polyphosphorhydrazone Janus Janus dendrimer dendrimer with with different different phos- phospho- phonates, and grafting to a TiO2 thin film, used as a fluorescent sensor for nitrophenols. nates, and grafting to a TiO2 thin film, used as a fluorescent sensor for nitrophenols. Considering the Considering the Janus Janusdendrimers dendrimersprepared, prepared,novel novel hybrid materials hybrid materialswere werecreated by created combining the fluorescent properties of the maleimide derivative and anchoring by combining the fluorescent properties of the maleimide derivative and anchoring the the ma- terial onto material a nanocrystalline onto a nanocrystalline mesoporous mesoporous titania thin thin titania film.film. The primary attribute The primary of these attribute of novel materials is their applicability as fluorescent probes. Simultaneously, these novel materials is their applicability as fluorescent probes. Simultaneously, titaniatitania films serve serve films as excellent supports as excellent for grafting supports organic organic for grafting molecules due to their molecules duechemical to their composi- chemical tion, and their mesoporous cavities and optical properties do not interfere composition, and their mesoporous cavities and optical properties do not interfere with those of with the dendrimer. The designed systems exhibit a significant quenching efficiency toward phenolic OH groups, thus suggesting their potential application as detectors for hazard- ous phenolic compounds, as illustrated in Scheme 14. Despite extensive research on the synthesis of dendrons using the AB5 derivative of cyclotriphosphazene, there are only two instances of employing these dendrons in the Molecules 2023, 28, 5570 14 of 18 those of the dendrimer. The designed systems exhibit a significant quenching efficiency toward phenolic OH groups, thus suggesting their potential application as detectors for hazardous phenolic compounds, as illustrated in Scheme 14. Despite extensive research on the synthesis of dendrons using the AB5 derivative of cyclotriphosphazene, there are only two instances of employing these dendrons in the synthesis of Janus dendrimers, as described by Fuchs et al. in 2015 [47]. Utiliz- ing the aforementioned methodology, two dendrons were synthesized, one containing five amino groups protected with tert-butyloxycarbonyl (Boc) groups and one carboxylic acid function, while the other contained five dansyl derivatives and one primary am- monium group (Scheme 15). Dansyl groups were chosen as the functional moiety for fluorescent labeling, as previously reported in the literature for fluorescent probes in dendrimers [48–50]. The synthesis of the Janus dendrimer proceeded through amide for- mation. Firstly, the carboxylic acid group of the first dendron was activated using TBTU (O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate) in the presence of DIPEA (N,N’-diisopropylethylamine). Subsequently, the activated dendron was reacted with the ammonium salt of the second dendron under basic conditions to form an amide bond (Scheme 15a). Finally, the resulting Janus dendrimer was treated with an excess of trifluoroacetic acid in dichloromethane to remove the Boc protecting group, resulting in a dendrimer with dansyl groups on one side and ammonium tags on the other. Another strategy to synthesize Janus dendrimers with dansyl and ammonium tags involved the use of a hydrazone bond (Scheme 15b). This approach was chosen because of the anticipated superior stability of hydrazones compared to that of amines in condensation reactions. For this purpose, two new dendrons were prepared: the first containing five Boc- protected primary amines and a hydrazide group, and the second containing five dansyl groups and one aldehyde group. The coupling of the two AB5 dendrons was achieved under basic conditions, resulting in the desired Janus dendrimer connected by a hydrazone linker. The obtained Janus dendrimer was again treated with trifluoroacetic acid to remove the Boc protecting group. The progress of the reaction was monitored by NMR and IR spectroscopy, observing the disappearance of the aldehyde signal and the formation of the hydrazone bond. Both synthesized Janus dendrimers were designed for applications in the fields of material science [51] and biology [52–54], leveraging the presence of fluorescent dansyl groups and ammonium tags, which provide water solubility. The fluorescent properties of the dendrimers were evaluated in dioxane as the solvent, demonstrating similar absorption and emission maxima wavelengths with a substantial Stokes shift resulting from the presence of the dansyl groups. A minimal spectral overlap was observed between the absorption and emission spectra, a highly advantageous feature for future biological applications, as it enables an improved separation of the probe’s inherent light and the light scattered by the sample. Of note, in 2011, Furer et al. conducted a density functional theory (DFT) study, as well as the IR and Raman spectra on the structure, of a dendron featuring five dansyl groups and a carbamate [55]. Computational studies involving structural optimization and normal mode analysis were performed, showing good agreement between the calculated geometrical parameters, harmonic vibrational frequencies, and experimental data. The calculations revealed that the dendron possesses a concave lens structure with a slightly non-planar cyclotriphosphazene core. Additionally, the intensity of the most prominent bands in the IR spectrum was reproduced by the calculations. Overall, the combined experimental and computational studies provided a detailed understanding of the dendron structure for the first time. five Boc-protected primary amines and a hydrazide group, and the second containing five dansyl groups and one aldehyde group. The coupling of the two AB5 dendrons was achieved under basic conditions, resulting in the desired Janus dendrimer connected by a hydrazone linker. The obtained Janus dendrimer was again treated with trifluoroacetic acid to remove the Boc protecting group. The progress of the reaction was monitored by Molecules 2023, 28, 5570 15 of 18 NMR and IR spectroscopy, observing the disappearance of the aldehyde signal and the formation of the hydrazone bond. Scheme 15. Synthesis of Janus dendrimers (based on method i) bearing dansyl groups in one end Scheme 15. Synthesis of Janus dendrimers (based on method i) bearing dansyl groups in one end and ammonium tags in the other through an (a) amide coupling; or (b) hydrazone linker; and (c) an and ammonium tags in the other through an (a) amide coupling; or (b) hydrazone linker; and expanded structure of a hybrid second-generation/first-generation Janus dendrimer with a hydra- (c) zoneanlinker. expanded structure of a hybrid second-generation/first-generation Janus dendrimer with a hydrazone linker. Both synthesized Janus dendrimers were designed for applications in the fields of 5. Conclusions material science [51] and biology [52–54], leveraging the presence of fluorescent dansyl Phosphorus Janus dendrimers offer a promising alternative to conventional dendritic systems due to their highly versatile functional groups The incorporation of multiple func- tionalities within a single dendrimer enables their utilization in multifaceted applications. In contrast to traditional organic Janus dendrimers, phosphorus analogs possess a notable advantage in terms of facile characterization, as illustrated in this review. Indeed, 31 P NMR is a very precious tool for assessing the purity of phosphorus-containing dendritic structures [56]. The characterization of dendritic compounds is never trivial, due to their repetitive structure, which often hampers any NMR characterization since the chemical environment is strictly identical at all layers. However, a slight difference in the density at each layer may slightly modify the geometry around the branching elements. 1 H and 13 C NMR are not sensitive to these subtle differences, contrarily to 31 P NMR, which is able to afford a different (sharp) signal for each dendritic layer, at least up to five different layers. Furthermore, the P=N-P=S linkages shown in several Schemes in this review are characterized by a set of two doublets, for which both the chemical shifts and the coupling Molecules 2023, 28, 5570 16 of 18 constant are very sensitive to their environment, and in particular to the reactions that occur on the constituents of this linkage, but also on the reactions that occur on the substituents of this linkage. Such behavior is particularly useful to characterize the sophisticated dendritic structures that are the Janus dendrimers. The pivotal aspect in the advancement of phosphorus Janus dendrimers lies in the coupling of dendrons, primarily accomplished through a core-to-core assembly, using straightforward and efficient reactions. Since the synthesized macromolecules from their corresponding dendrons can be challenging, it is highly desirable to employ quantitative reactions that do not generate side products. In this comprehensive review, we have presented various methodologies described so far for the preparation of these systems. The most extensively explored approach involves the coupling of dendrons possessing vinyl and amine groups through a Michael addition reaction. However, alternative reactions have also been investigated, such as the formation of amide or hydrazone bonds, as well as the utilization of the Staudinger reaction. Despite the considerable progress made in the development of these systems, there remains ample scope for synthesizing such architectures using novel approaches. In this regard, the integration of a “click” chemistry between azide and alkyne holds tremen- dous potential, as it could enable the generation of complex dendritic structures using straightforward methodologies. Lastly, the phosphorus Janus dendrimers discussed in this review have demonstrated applicability in various fields, particularly in materials science. Nonetheless, numerous other applications could be targeted in the future, particularly in critical areas such as catalysis. Author Contributions: Conceptualization, A.-M.C.; writing—original draft preparation, J.C.-S.; writing—review and editing, J.C.-S., A.K., K.G., A.-M.C. and R.M.S.; supervision, A.K. and R.M.S.; project administration, R.M.S. and A.-M.C.; funding acquisition, K.G., A.-M.C. and R.M.S. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by the European Union’s Horizon 2020 research and innova- tion program under the Marie Skłodowska-Curie grant agreement No. 860322 for the ITN-EJD “Coordination Chemistry Inspires Molecular Catalysis” (CCIMC). Institutional Review Board Statement: Not applicable. Data Availability Statement: Not Applicable. Acknowledgments: Thanks are due to Generalitat de Catalunya (2021 SGR 00064) and Ministerio de Ciencia, Innovación y Universidades (PID2019-106171RB-I00) for financial support. Conflicts of Interest: The authors declare no conflict of interest. References 1. Caminade, A.-M.; Turrin, C.-O.; Laurent, R.; Ouali, A.; Delavaux-Nicot, B. Dendrimers: Towards Catalytic, Material and Biomedical Uses, 1st ed.; John Wiley & Sons Ltd.: Chichester, UK, 2011. 2. Tomalia, D.A.; Baker, H.; Dewald, J.; Hall, M.; Kallos, G.; Martin, S.; Roeck, J.; Ryder, J.; Smith, P. A New Class of Polymers: Starburst-Dendritic. Polym. J. 1985, 17, 117–132. [CrossRef] 3. Lee, C.C.; MacKay, J.A.; Fréchet, J.M.J.; Szoka, F.C. Designing Dendrimers for Biological Applications. Nat. Biotechnol. 2005, 23, 1517–1526. [CrossRef] [PubMed] 4. Pedziwiatr-Werbicka, E.; Milowska, K.; Dzmitruk, V.; Ionov, M.; Shcharbin, D.; Bryszewska, M. Dendrimers and Hyperbranched Structures for Biomedical Applications. Eur. Polym. J. 2019, 119, 61–73. [CrossRef] 5. Riegert, D.; Bareille, L.; Laurent, R.; Majoral, J.P.; Caminade, A.-M.; Chaumonnot, A. Silica Functionalized by Bifunctional Dendrimers: Hybrid Nanomaterials for Trapping CO2 . Eur. J. Inorg. Chem. 2016, 19, 3103–3110. [CrossRef] 6. Ali, B.M.; Kumar, K.A.; Sultan Nasar, A.S. Fifth Generation Polyurethane Dendrimers Decorated with Protected Amine, Free Amine and Blocked Isocyanate End Groups: Synthesis and Electrolytic Performance to Increase the Efficiency of Dye-Sensitized Solar Cell. ChemistrySelect 2019, 4, 12983–12991. [CrossRef] 7. Reek, J.N.H.; Arévalo, S.; van Heerbeek, R.; Kamer, P.C.J.; van Leeuwen, P.W.N.M. Dendrimers in Catalysis. Adv. Catal. 2006, 49, 71–151. [CrossRef] 8. Neumann, P.; Dib, H.; Caminade, A.-M.; Hey-Hawkins, E. Redox Control of a Dendritic Ferrocenyl-Based Homogeneous Catalyst. Angew. Chem. Int. Ed. 2015, 54, 311–314. [CrossRef] Molecules 2023, 28, 5570 17 of 18 9. Caminade, A.-M.; Laurent, R. Homogeneous Catalysis with Phosphorus Dendrimer Complexes. Coord. Chem. Rev. 2019, 389, 59–72. [CrossRef] 10. Thakare, S.; Shaikh, A.; Bodas, D.; Gajbhiye, V. Application of Dendrimer-Based Nanosensors in Immunodiagnosis. Colloids Surf. B 2022, 209, 112174. [CrossRef] 11. Satija, J.; Sai, V.V.R.; Mukherji, S. Dendrimers in Biosensors: Concept and Applications. J. Mater. Chem. 2011, 21, 14367–14386. [CrossRef] 12. Petriccone, M.; Laurent, R.; Turrin, C.-O.; Sebastián, R.M.; Caminade, A.-M. Specific Bifunctionalization on the Surface of Phosphorus Dendrimers Syntheses and Properties. Organics 2022, 3, 240–261. [CrossRef] 13. Najafi, F.; Salami-Kalajahi, M.; Roghani-Mamaqani, H. Janus-Type Dendrimers: Synthesis, Properties, and Applications. J. Mol. Liq. 2022, 347, 118396. [CrossRef] 14. Caminade, A.-M.; Laurent, R.; Delavaux-Nicot, B.; Majoral, J.P. “Janus” Dendrimers: Syntheses and Properties. New J. Chem. 2012, 36, 217–226. [CrossRef] 15. de Gennes, P.G. Nanoparticles and Dendrimers: Hopes and Illusions. Croat. Chem. Acta 1998, 71, 833–836. Available online: https://hrcak.srce.hr/132422 (accessed on 21 June 2023). 16. Yanagimoto, Y.; Takaguchi, Y.; Tuboi, S. Novel Synthesis of Surface-Block Dendrimer Using [4+4] Photocycloaddition of Anthryl Dendrons. Polym. J. 2006, 38, 1230–1236. [CrossRef] 17. Nierengarten, J.F.; Eckert, J.F.; Rio, Y.; Del Pilar Carrion, M.; Gallani, J.L.; Guillon, D. Amphiphilic Diblock Dendrimers: Synthesis and Incorporation in Langmuir and Langmuir-Blodgett Films. J. Am. Chem. Soc. 2001, 123, 9743–9748. [CrossRef] 18. Wooley, K.L.; Hawker, C.J.; Fréchet, J.M.J. Polymers with Controlled Molecular Architecture: Control of Surface Functionality in the Synthesis of Dendritic Hyperbranched Macromolecules Using the Convergent Approach. J. Chem. Soc. Perkin Trans. 1 1991, 5, 1059–1076. [CrossRef] 19. Hawker, C.J.; Wooley, K.L.; Fréchet, J.M.J. Unimolecular Micelles and Globular Amphiphiles: Dendritic Macromolecules as Novel Recyclable Solubilization Agents. J. Chem. Soc. Perkin Trans. 1 1993, 12, 1287–1297. [CrossRef] 20. Wooley, K.L.; Hawker, C.J.; Fréchet, J.M.J. Unsymmetrical Three-Dimensional Macromolecules: Preparation and Characterization of Strongly Dipolar Dendritic Macromolecules. J. Am. Chem. Soc. 1993, 115, 11496–11505. [CrossRef] 21. Wooley, K.L.; Hawker, C.J.; Pochan, J.M.; Fréchet, J.M.J. Physical Properties of Dendritic Macromolecules: A Study of Glass Transition Temperature. Macromolecules 1993, 26, 1514–1519. [CrossRef] 22. Bo, Z.; Rabe, J.P.; Schlüter, A.D. A Poly(para-phenylene) with Hydrophobic and Hydrophilic Dendrons: Prototype of an Amphiphilic Cylinder with the Potential to Segregate Lengthwise. Angew. Chem. Int. Ed. 1999, 38, 2370–2372. [CrossRef] 23. Aoi, K.; Itoh, K.; Okada, M. Divergent/Convergent Joint Approach with a Half-Protected Initiator Core To Synthesize Surface- Block Dendrimers. Macromolecules 1997, 30, 8072–8074. [CrossRef] 24. Rosati, M.; Acocella, A.; Pizzi, A.; Turtù, G.; Neri, G.; Demitri, N.; Raffaini, G.; Donnio, B.; Zerbetto, F.; Baldelli Bombelli, F.; et al. Janus-Type Dendrimers Based on Highly Branched Fluorinated Chains with Tunable Self-Assembly and 19 F Nuclear Magnetic Resonance Properties. Macromolecules 2022, 55, 2486–2496. [CrossRef] 25. Căta, A.; Ienas, cu, I.M.C.; Ştefănut, , M.N.; Ros, u, D.; Pop, O.R. Properties and Bioapplications of Amphiphilic Janus Dendrimers: A Review. Pharmaceutics 2023, 15, 589. [CrossRef] [PubMed] 26. Maraval, V.; Laurent, R.; Donnadieu, B.; Mauzac, M.; Caminade, A.-M.; Majoral, J.P. Rapid Synthesis of Phosphorus-Containing Dendrimers with Controlled Molecular Architectures: First Example of Surface-Block, Layer-Block, and Segment-Block Den- drimers Issued from the Same Dendron. J. Am. Chem. Soc. 2000, 122, 2499–2511. [CrossRef] 27. Maraval, V.; Laurent, R.; Merino, S.; Caminade, A.-M.; Majoral, J.P. Michael-Type Addition of Amines to the Vinyl Core of Dendrons—Application to the Synthesis of Multidendritic Systems. Eur. J. Org. Chem. 2000, 21, 3555–3568. [CrossRef] 28. Launay, N.; Caminade, A.-M.; Majoral, J.P. Synthesis and Reactivity of Unusual Phosphorus Dendrimers. A Useful Divergent Growth Approach Up to the Seventh Generation. J. Am. Chem. Soc. 1995, 117, 3282–3283. [CrossRef] 29. Galliot, C.; Prévoté, D.; Caminade, A.-M.; Majoral, J.P. Polyaminophosphines Containing Dendrimers. Syntheses and Characteri- zations. J. Am. Chem. Soc. 1995, 117, 5470–5476. [CrossRef] 30. Maraval, V.; Maraval, A.; Spataro, G.; Caminade, A.-M.; Majoral, J.P.; Kim, D.H.; Knoll, W. Design of Tailored Multi-Charged Phosphorus Surface-Block Dendrimers. New J. Chem. 2006, 30, 1731–1736. [CrossRef] 31. Blanzat, M.; Turrin, C.O.; Aubertin, A.M.; Couturier-Vidal, C.; Caminade, A.-M.; Majoral, J.P.; Rico-Lattes, I.; Lattes, A. Den- dritic Catanionic Assemblies: In Vitro Anti-HIV Activity of Phosphorus-Containing Dendrimers Bearing Galβ1cer Analogues. ChemBioChem 2005, 6, 2207–2213. [CrossRef] 32. Solassol, J.; Crozet, C.; Perrier, V.; Leclaire, J.; Béranger, F.; Caminade, A.-M.; Meunier, B.; Dormont, D.; Majoral, J.P.; Lehmann, S. Cationic Phosphorus-Containing Dendrimers Reduce Prion Replication Both in Cell Culture and in Mice Infected with Scrapie. J. Gen. Virol. 2004, 85, 1791–1799. [CrossRef] [PubMed] 33. Kim, B.S.; Lebedeva, O.V.; Kim, D.H.; Caminade, A.-M.; Majoral, J.P.; Knoll, W.; Vinogradova, O.I. Assembly and Mechanical Properties of Phosphorus Dendrimer/Polyelectrolyte Multilayer Microcapsules. Langmuir 2005, 21, 7200–7206. [CrossRef] [PubMed] 34. Lee, O.J.; Maraval, V.; Caminade, A.-M.; Chung, K.; Lau, K.H.A.; Shin, K.; Majoral, J.P.; Knoll, W.; Kim, D.H. Layer-by-Layer Self-Assembly of Bisdendrons: An Unprecedented Route to Multilayer Thin Films. Macromol. Res. 2016, 24, 851–855. [CrossRef] 35. Staudinger, H.; Hauser, E. Über Neue Organische Phosphorverbindungen IV Phosphinimine. Helv. Chim. Acta 1921, 2, 861–887. [CrossRef] 36. Gololobov, Y.G.; Zhmurova, I.N.; Kasukhin, L.F. Sixty Years of Staudinger. Tetrahedron 1981, 37, 437–472. [CrossRef] 37. Gololobov, Y.G. Recent Advances in the Staudinger Reaction. Tetrahedron 1992, 48, 1353–1406. [CrossRef] Molecules 2023, 28, 5570 18 of 18 38. Fresneda, P.M.; Molina, P. Application of Iminophosphorane-Based Methodologies for the Synthesis Of Natural Products. Synlett 2004, 1, 1–17. [CrossRef] 39. Brauge, L.; Magro, G.; Caminade, A.-M.; Majoral, J.P. First Divergent Strategy Using Two AB2 Unprotected Monomers for the Rapid Synthesis of Dendrimers. J. Am. Chem. Soc. 2001, 123, 6698–6699. [CrossRef] 40. Gottis, S.; Rodriguez, L.I.; Laurent, R.; Angurell, I.; Seco, M.; Rossell, O.; Majoral, J.P.; Caminade, A.-M. Janus Carbosi- lane/Phosphorhydrazone Dendrimers Synthesized by the ‘Click’ Staudinger Reaction. Tetrahedron Lett. 2013, 54, 6864–6867. [CrossRef] 41. Maraval, V.; Sebastián, R.M.; Ben, F.; Laurent, R.; Caminade, A.-M.; Majoral, J.P. Varying Topology of Dendrimers—A New Approach toward the Synthesis of Di-Block Dendrimers. Eur. J. Inorg. Chem. 2001, 7, 1681–1691. [CrossRef] 42. Mitjaville, J.; Caminade, A.-M.; Mathieu, R.; Majoral, J. New Synthetic Strategies for Phosphorus-Containing Cryptands and the First Phosphorus Spherand Type Compound. J. Am. Chem Soc. 1994, 116, 5007–5008. [CrossRef] 43. Caminade, A.-M.; Hameau, A.; Majoral, J.-P. The specific functionalization of cyclotriphosphazene for the synthesis of smart dendrimers. Dalton Trans. 2016, 45, 1810–1822. [CrossRef] 44. Maraval, V.; Caminade, A.-M.; Majoral, J.P.; Blais, J.C. Dendrimer Design: How to Circumvent the Dilemma of a Reduction of Steps or an Increase of Function Multiplicity? Angew. Chem. Int. Ed. 2003, 42, 1822–1826. [CrossRef] 45. Zibarov, A.; Oukhrib, A.; Catot, J.A.; Turrin, C.O.; Caminade, A.-M. AB5 Derivatives of Cyclotriphosphazene for the Synthesis of Dendrons and Their Applications. Molecules 2021, 26, 4017. [CrossRef] [PubMed] 46. Martínez-Ferrero, E.; Franc, G.; Mazères, S.; Turrin, C.O.; Boissière, C.; Caminade, A.-M.; Majoral, J.P.; Sanchez, C. Optical Properties of Hybrid Dendritic-Mesoporous Titania Nanocomposite Films. Chem. Eur. J. 2008, 14, 7658–7669. [CrossRef] 47. Fuchs, S.; Pla-Quintana, A.; Mazères, S.; Caminade, A.-M.; Majoral, J.P. Cationic and Fluorescent “Janus” Dendrimers. Org. Lett. 2008, 10, 4751–4754. [CrossRef] 48. Branchi, B.; Ceroni, P.; Bergamini, G.; Balzani, V.; Maestri, M.; Van Heyst, J.; Lee, S.K.; Luppertz, F.; Vögtle, F. A Cyclam Core Dendrimer Containing Dansyl and Oligoethylene Glycol Chains in the Branches: Protonation and Metal Coordination. Chem. Eur. J. 2006, 12, 8926–8934. [CrossRef] 49. Fuchs, S.; Otto, H.; Jehle, S.; Henklein, P.; Schlüter, A.D. Fluorescent Dendrimers with a Peptide Cathepsin B Cleavage Site for Drug Delivery Applications. Chem. Commun. 2005, 1, 1830–1832. [CrossRef] 50. Fuchs, S.; Kapp, T.; Otto, H.; Schöneberg, T.; Franke, P.; Gust, R.; Schüter, A.D. A Surface-Modified Dendrimer Set for Potential Application as Drug Delivery Vehicles: Synthesis, In Vitro Toxicity, and Intracellular Localization. Chem. Eur. J. 2004, 10, 1167–1192. [CrossRef] [PubMed] 51. Feng, C.L.; Zhong, X.H.; Steinhart, M.; Caminade, A.-M.; Majoral, J.P.; Knoll, W. Functional Quantum-Dot/Dendrimer Nanotubes for Sensitive Detection of DNA Hybridization. Small 2008, 4, 566–571. [CrossRef] 52. Mongin, O.; Krishna, T.R.; Werts, M.H.V.; Caminade, A.-M.; Majoral, J.P.; Blanchard-Desce, M. A Modular Approach to Two- Photon Absorbing Organic Nanodots: Brilliant Dendrimers as an Alternative to Semiconductor Quantum Dots? Chem. Commun. 2006, 8, 915–917. [CrossRef] [PubMed] 53. Rolland, O.; Griffe, L.; Poupot, M.; Maraval, A.; Ouali, A.; Coppel, Y.; Fournié, J.J.; Bacquet, G.; Turrin, C.O.; Caminade, A.-M.; et al. Tailored Control and Optimisation of the Number of Phosphonic Acid Termini on Phosphorus-Containing Dendrimers for the Ex-Vivo Activation of Human Monocytes. Chem. Eur. J. 2008, 14, 4836–4850. [CrossRef] [PubMed] 54. Griffe, L.; Poupot, M.; Marchand, P.; Maraval, A.; Turrin, C.O.; Rolland, O.; Métivier, P.; Bacquet, G.; Fournié, J.J.; Caminade, A.-M.; et al. Multiplication of Human Natural Killer Cells by Nanosized Phosphonate-Capped Dendrimers. Angew. Chem. Int. Ed. 2007, 46, 2523–2526. [CrossRef] [PubMed] 55. Furer, V.L.; Vandyukova, I.I.; Vandyukov, A.E.; Fuchs, S.; Majoral, J.P.; Caminade, A.-M.; Kovalenko, V.I. DFT Study of Structure, IR and Raman Spectra of the Fluorescent “Janus” Dendron Built from Cyclotriphosphazene Core. J. Mol. Struct. 2011, 1005, 25–30. [CrossRef] 56. Caminade, A.M.; Laurent, R.; Turrin, C.O.; Rebout, C.; Delavaux-Nicot, B.; Ouali, A.; Zablocka, M.; Majoral, J.P. Phosphorus dendrimers as viewed by 31 P NMR spectroscopy; synthesis and characterization. Comp. Rend. Chimie 2010, 13, 1006–1027. [CrossRef] Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.